Targeting Hypoxia-Inducible Factors for Antiangiogenic Cancer Therapy

Sergio Rey; Luana Schito; Bradly G Wouters; Scott Eliasof; Robert S Kerbel

doi:10.1016/j.trecan.2017.05.002

Targeting Hypoxia-Inducible Factors for Antiangiogenic Cancer Therapy

Trends Cancer. 2017 Jul;3(7):529-541. doi: 10.1016/j.trecan.2017.05.002. Epub 2017 Jun 10.

Authors

Sergio Rey¹, Luana Schito², Bradly G Wouters³, Scott Eliasof⁴, Robert S Kerbel⁵

Affiliations

¹ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. Electronic address: sergio.rey@ls2r.science.
² Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. Electronic address: luana.schito@ls2r.science.
³ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, ON, Canada; Radiation Oncology, University of Toronto, ON, Canada.
⁴ Cerulean Pharma Inc., Waltham, MA, USA.
⁵ Radiation Oncology, University of Toronto, ON, Canada; Biological Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada.

PMID: 28718406
DOI: 10.1016/j.trecan.2017.05.002

Abstract

Hypoxia (low O₂) is a pathobiological hallmark of solid cancers, resulting from the imbalance between cellular O₂ consumption and availability. Hypoxic cancer cells (CCs) stimulate blood vessel sprouting (angiogenesis), aimed at restoring O₂ delivery to the expanding tumor masses through the activation of a transcriptional program mediated by hypoxia-inducible factors (HIFs). Here, we review recent data suggesting that the efficacy of antiangiogenic (AA) therapies is limited in some circumstances by HIF-dependent compensatory responses to increased intratumoral hypoxia. In lieu of this evidence, we discuss the potential of targeting HIFs as a strategy to overcome these instances of AA therapy resistance.

Keywords: HIF; antiangiogenic therapy; hypoxia; targeted therapy; topoisomerase inhibitors; tumor angiogenesis.

Publication types

Review

MeSH terms

Angiogenesis Inhibitors / pharmacology
Angiogenesis Inhibitors / therapeutic use*
Basic Helix-Loop-Helix Transcription Factors / antagonists & inhibitors*
Basic Helix-Loop-Helix Transcription Factors / metabolism
DNA Topoisomerases, Type I / metabolism
Drug Repositioning / methods
Drug Repositioning / trends
Drug Resistance, Neoplasm / drug effects
Humans
Hypoxia / pathology
Molecular Targeted Therapy / methods
Nanoconjugates
Neoplasms / blood supply
Neoplasms / drug therapy*
Neoplasms / pathology
Neovascularization, Pathologic / drug therapy*
Oligonucleotides / pharmacology
Oligonucleotides / therapeutic use
Oligonucleotides, Antisense / pharmacology
Oligonucleotides, Antisense / therapeutic use
Signal Transduction / drug effects
Topoisomerase Inhibitors / pharmacology
Topoisomerase Inhibitors / therapeutic use*
Treatment Outcome

Substances

Angiogenesis Inhibitors
Basic Helix-Loop-Helix Transcription Factors
EZN 2968
Nanoconjugates
Oligonucleotides
Oligonucleotides, Antisense
Topoisomerase Inhibitors
DNA Topoisomerases, Type I
TOP1 protein, human